Dystonia Linked to EIF4A2 Haploinsufficiency: A Disorder of Protein Translation Dysfunction

Abstract

BackgroundProtein synthesis is a tightly controlled process, involving a host of translation‐initiation factors and microRNA‐associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental‐delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability.ObjectiveWe sought to characterize the role of EIF4A2 variants in dystonic conditions.MethodsWe undertook an unbiased search for likely deleterious variants in mutation‐constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient‐derived fibroblasts.ResultsWe report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence‐ to adulthood‐onset dystonia with tremor. In patient‐derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4‐Not, the complex that interacts with eIF4A2 to mediate microRNA‐dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4‐Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia‐affected pedigrees.ConclusionsOur findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia‐tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later‐onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Large‐Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes

“…Notably, a subset of the patients (n = 114) included here were screened for VPS16 variants by Sanger sequencing, and indeed, one carrier of a clearly pathogenic, truncating variant was found. 30 Other, more recently reported genes for isolated dystonia, such as EIF2AK2, 31 AOPEP, 32 and EIF4A2, 33 or combined dystonia, such as KCTD17 among many others, 34,35 have not yet been targeted. The best way to screen dystonia patients comprehensively is to perform exome or even genome sequencing.…”

The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia

“…A subsequent human genetic association of dystonia with mutations in the EIF2AK2 gene, which encodes the PKR kinase ( 23 – 27 ), further established the link between dystonia and the ISR. While a recent association of dystonia with mutation in the EIF4A2 gene ( 28 ) highlights the functional intersection between dystonia and the translational initiation process. The encoded protein, eIF4A-2, is necessary to coordinate complexing of the mRNA with the eIF2 complex–associated, methionine tRNA–charged 43S ribosome.…”

“… 32 ]). Human genes associated with effects on the ISR, or translational initiation, that present with clinical phenotypes of dystonia include PKR ( EIF2AK2 ) ( 23 – 27 ), EIF2B ( 42 , 95 ), ATF4 ( 5 ), EIF4A2 ( 28 ), and a range of tRNA synthetase genes associated with mitochondrial disorders ( 33 – 41 ) (e.g., AARS1 , AARS2 , CARS2 , EARS2 , WARS2 , TARS2 ). Activation of the ISR results in phosphorylation of the α subunit of eIF2 and reduces the rate of eIF2B-mediated GDP/GTP exchange of eIF2, preventing the formation of the ternary complex (TC) (GTP-eIF2-Met tRNA).…”

<strong>Dystonia, Tremor, and Dystonic Tremor</strong>

“…Some literature employs a hybrid approach, emphasizing jerkiness and irregular qualities along with coexisting dystonic posturing [14,15]. Still other literature has adopted alternative terminology, such as jerky dystonia [16][17][18], dystonia-tremor syndrome [19][20][21], dystonia with tremor [22][23][24], and tremulous dystonia [25,26]. Varying viewpoints are evident even among movement disorder specialists [27,28].…”